The discovery of RNA interference (RNAi) is considered one of the most exciting and significant medical breakthroughs of recent years. With the ability to selectively silence any gene in the genome, RNAi not only provides an indispensable research tool for unravelling gene function, but also offers potential for the development of novel therapeutics that silence specific genes involved in disease.
RNAi is a naturally occurring cellular mechanism for gene regulation. The presence of double stranded RNA (dsRNA) in a cell is recognised as ‘foreign’ and is destroyed together with any single stranded RNA including messenger RNA (mRNA) of the same sequence. Destruction of mRNA results in the post transcriptional inhibition of gene expression and the prevention of protein synthesis. RNAi is a potent and highly selective process that may, in principle, be exploited to silence any gene of interest using synthetic short interfering RNA (siRNA). Non-target genes are unaffected, reducing the potential for unwanted side effects.
Perhaps the greatest potential use of siRNA-induced RNAi lies in the development of a new class of RNAi-based therapeutics. These could silence any selected gene influencing the initiation or progression of a disease or disease process – from viral genes, oncogenes and inherited defective genes, to genes that contribute to multi-factorial diseases such as cancer, heart disease, diabetes, and degenerative disorders.
Synthetic siRNA may be used to inhibit the expression of any disease-related gene by exploiting the naturally occurring RNAi process. The potential power and sensitivity of RNAi therapeutics lies in its ability to silence targeted genes only. RNAi also has the advantage that non-druggable targets are no longer a limitation, as RNAi therapeutics aim to affect a target gene’s expression rather than just its activity or localisation.
In common with conventional therapeutics, siRNA must reach the targeted cells and needs to be able to penetrate the cell membrane and survive long enough inside the cell in order to exert its effects. This challenge of exploiting RNAi for therapeutic purposes is addressed by our proprietary lipoplex-based delivery systems AtuPLEX®, DACC, HepaPLEX and our specially modified AtuRNAi® siRNA molecules.
Our patented RNAi platform is known as AtuRNAi®. It is made up of highly potent, chemically stabilised siRNA molecules which offer greater stability and better tolerability over conventional siRNA molecules.
AtuRNAi®’s unique RNAi assets include:
- structural features for RNAi molecules
- specific design rules for increased potency
- reduced off-target effects of siRNA sequences
The same scale-up process for all AtuRNAi® molecules also allows faster preclinical development and lower costs.
AtuRNAi® has been chemically modified to result in a blunt-ended, chemically stabilised molecule which contains only naturally-occurring RNA. This modification pattern offers advantages over standard siRNA such as stability against nuclease degradation and prevention from innate immune response.
The result of using naturally occurring building blocks for AtuRNAi® is the elimination of toxic metabolites, lower manufacturing costs, increased yield and faster synthesis. Unlike most existing therapeutics where each new chemical entity has a distinct composition and synthetic protocol, the structure and synthesis of AtuRNAi® type siRNA is similar.